RNA interference screening identifies clathrin-B and cofilin-1 as mediators of MT1-MMP in endometrial cancer
RNA interference screening identifies clathrin-B and cofilin-1 as mediators of MT1-MMP in endometrial cancer
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DOI：
10.1016/j.yexcr.2018.07.031
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发表时间：
2018-09-15
影响因子：
3.7
通讯作者：
Syed, Viqar
中科院分区：
文献类型：
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作者：
Baker, Tabari M.;Waheed, Sana;Syed, Viqar
基质金属蛋白酶（matrix metalloproteinases，MMPs）参与肿瘤的侵袭和转移。鉴于其多种肿瘤促进作用，MMPs是治疗转移性癌症的有希望的靶点。使用140个膜运输基因的siRNA文库筛选，我们在HEC-1B和石川癌细胞中鉴定了41个降低金属蛋白酶活性的基因。两种癌细胞系中共有的16个基因降低了MMP活性，涉及货物分选，囊泡形成和囊泡回收。选择前两个基因网格蛋白-B和cofilin-1用于事后功能研究。在癌细胞中证实了这两种基因的较高表达，并且用各自的siRNA敲低抑制了它们的侵袭潜力和基质金属蛋白酶活性。膜1型基质金属蛋白酶（MT 1-MMP）是一种重要的蛋白酶，是肿瘤侵袭和转移的调节因子。在网格蛋白-B和cofilin-1敲低的癌细胞中观察到MT 1-MMP表达和活性的显著降低，这与侵袭伪足形成蛋白的表达的显著降低相关。我们的研究结果表明，网格蛋白B和cofilin-1的表达减少，减少MT 1-MMP的表达，导致MT 1-MMP在细胞表面的衰减，从而抑制肿瘤细胞的侵袭和转移。
The matrix metalloproteinases (MMPs) are implicated in tumor invasion and metastasis. Given their multiple tumor promoting roles, MMPs are promising targets for the treatment of metastatic cancer. Using a siRNA library screen of 140 membrane trafficking genes, we identified 41 genes in HEC-1B and 36 in Ishikawa cancer cells that decreased metalloproteinases activity. The 16 genes common in both cancer cell lines that decreased MMPs activity are involved in cargo sorting, vesicle formation and vesicle recycling. The top two genes clathrin-B and cofilin-1 were chosen for post hoc functional studies. Higher expression of both genes was confirmed in cancer cells and knockdown with respective siRNAs inhibited their invasive potential and matrix metalloproteinases activity. Membrane Type 1- Matrix Metalloproteinase (MT1-MMP) is a master switch proteinase and regulator of invasion and metastasis. A marked decrease in MT1-MMP expression and activity was seen in clathrin-B and cofilin-1 knockdown cancer cells which was associated with a marked decreased expression of invadopodia formation proteins. Our results suggest that the decreased expression of clathrin-B and cofilin-1 decreases the expression of MT1-MMP and results in attenuation of MT1-MMP at the cell surface, thus inhibiting tumor cell invasion and metastasis.